Hereditary nonpolyposis colorectal cancer (HNPCC) poses a major public health problem wherein very little is known about the gross, microscopic, or histochemical premorbid pathology of the colonic mucosa in at risk patients. We shall take advantage of our resource of well-documented HNPCC kindreds to select 100 patients between the ages of 30 and 50 who are at 50% risk for this disease. Each of these individuals will undergo colonoscopy with multiple mucosal biopsies from cecum to rectum. Similar studies will be obtained on 100 patients with nonfamilial colon cancer and 20 normal controls with negative family histories of colon cancer. Detailed biochemical (lectin binding, tritiated thymidine uptake) and histopathologic (dysplastic changes, adenomatous changes, alterations in mucin secretion) parameters will be assessed in these tissues in a double-binded manner. Concurrently we will provide intensive education about the natural history of HNPCC and our strategies for surveillance and management of these patients and their relatives for their family physicians as well as followup as to the effect of such intervention. OUr experimental design will provide a basis for statistical analysis of the study population, the comparison group, and normal controls, utilizing the SYSDAT data analysis program for discriminant analysis to drive the function(s) that best differentiates cancer affected individuals from controls. That function will then be applied to the at risk group in order to determine if this group is heterogeneous and regard to the pathologic variables,and if there is bimodality of the discriminant score in the at risk group. These methods will allow comparison of the various parameters studies between the at risk, affected, and normal controls. We believe that this project could provide abundant new information as to the spectrum of premalignant abnormalities in HNPCC. These findings, coupled with education and surveillance programs, could have significant implications for cancer etiology, carcinogenesis, and control for the general population.